Biopolymers are biocompatible polymers that are useful for a wide variety of biomedical applications, such as for surgical aids, to prevent or reduce the formation of surgical adhesions, and for drug delivery applications. Many biopolymers are naturally occurring substances found in the body, and therefore do not have any unacceptable toxic or injurious effects on biological function. An example of such a biopolymer is hyaluronic acid (“HA”), a naturally occurring mucopolysaccharide found, for example, in synovial fluid, in vitreous humor, in blood vessel walls and the umbilical cord, and in other connective tissues. Hyaluronic acid consists of alternating N-acetyl-D-glucosamine and D-glucuronic acid residues joined by alternating β 1-3 glucuronidic and β 1-4 glucosaminidic bonds, so that the repeating unit is -(1→4)-β-D-GlcA-(1→3)-β-D-GlcNAc-. In water, hyaluronic acid dissolves to form a highly viscous fluid. The molecular weight of hyaluronic acid isolated from natural sources generally falls within the range of 5×104 up to 1×107 daltons.
U.S. Pat. No. 4,582,865, to Balazs et al. states, inter alia, that cross-linked gels of HA can slow the release of a low molecular weight substance that is dispersed therein but not covalently attached to the gel macromolecular matrix. See, also, U.S. Pat. No. 4,636,524, which contains a disclosure of related technology. Both of these patents describe HA compositions in which the HA is crosslinked by reaction with divinyl sulfone, and the use of the crosslinked HA compositions in drug delivery applications.
R. V. Sparer et al., 1983, Chapter 6, pages 107-119, in T. J. Roseman et al., Controlled Release Delivery Systems, Marcel Dekker, Inc., New York, describes sustained release of chloramphenicol covalently attached to hyaluronic acid by an ester linkage, either directly or in an ester complex including an alanine bridge as an intermediate linking group. The HA is modified by attaching cysteine residues to the HA via amide bonds, and then the cysteine-modified HA is crosslinked by forming disulfide bonds between the attached cysteine residues. Similarly, I. Danishefsky et al., 1971, in Carbohydrate Res., Vol. 16, pages 199-205, describe the modification of a mucopolysaccharide by converting the carboxyl groups of the mucopolysaccharide into substituted amides by reacting the mucopolysaccharide with an amino acid ester in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (“EDC”) in aqueous solution. See, also, U.S. Pat. No. 4,937,270 and U.S. Pat. No. 5,760,220 which describe the modification of hyaluronic acid by reaction of the carboxyl groups of the biopolymer with a nucleophile to produce a water insoluble amide, and the use of those compositions for controlled release drug delivery.
A series of patents assigned to VivoRx Pharmaceuticals, Inc., describe compositions for the in vivo delivery of insoluble pharmaceutically active agents. Delivery of the drug substances is achieved, for instance, by encasing the active agent in a polymeric shell formed from a biocompatible polymer. The biocompatible polymer may be protein, lipid, DNA molecule or polysacharide, and the pharmaceutically active agent may be a therapeutic protein such as taxol. The polymer contains covalently attached sulfhydryl groups or disulfide linkages which can be crosslinked to form disulfide bonds. The polymeric shell is formed using ultrasonic irradiation techniques. These compositions are described as being less toxic, being more soluble, and having improved targeting as compared to prior art compositions. Relevant VivoRx patents include U.S. Pat. Nos. 5,498,421; 5,439,686; 5,362,478; 5,635,207; 5,560,933; 5,635,207 and 5,639,473.
U.S. Pat. No. 5,496,872 relates to biocompatible and biodegradable crosslinkable polymers having reactive thiol groups. The reactive thiol groups can be crosslinked to form disulfide linkages between adjacent molecules, resulting in a three dimensional network. These polymers can be used for binding tissues or binding tissues with implanted biomaterials.
U.S. Pat. No. 5,932,552 describes a keratin hydrogel having biomedical applications. The hydrogel is formed from crosslinked keratin bound by disulfide linkages. Among the biomedical applications described in the patent are uses of the hydrogels for cell scaffolding in tissue repair.
U.S. Pat. Nos. 5,354,853 and 5,451,661 describe, respectively, the preparation of phospholipid-saccharide conjugates, and lipids conjugated to biologically active agents such as peptides, proteins and nucleic acids. These conjugates are described as being particularly useful in drug delivery applications.
U.S. Pat. No. 5,902,795, to Toole et al., discloses hyaluronic acid oligosaccharides, having between one and sixteen repeating units, which are used to treat tumors in mammals. The patent states that the oligosaccharides act to reduce the level of membrane-associated hyaluronan-binding proteins, which are expressed on the surface of certain tumor cells during cell migration. The treatment is believed to reduce the incidence of tumor metastasis in the mammals.
A. Burnkop-Schnurch et al., J. Controlled Release, 2000, 66, 39, describes the synthesis of carboxymethyl cellulose (“CMC”) and polycarbophil modified with L-cysteine using carbodiimide chemistry. The polymers are reacted with the cysteine to form an amide bond between the primary amino group of the amino acid and the carboxylic acid of the polymer. The thiolated polymers were allowed to oxidize to form disulfide bridges. The dissolution of these tablets, both with and without drugs, was analyzed. The tablets were found to have improved stability and viscoelasticity.
Copending U.S. patent application Ser. No. 09/430,857, now abandoned, relates to surfaces that have been modified by the attachment of hyaluronic acid. The surface can be part of a medical device, such as a stent or a surgical tubing. The surface is modified to include a reactive amino group that reacts with a derivatized hyaluronic acid. The modified devices and instruments are hydrophilic, and have anti-fouling and anti-platelet adhesion characteristics, thereby producing a reduction in risks associated with thrombosis.
The conjugated biopolymers of this invention represent a significant improvement over drug delivery vehicles of the prior art due, in part, to the site-specific reaction between the biopolymer and the therapeutic agent which increases the stability and activity of the therapeutic agent upon delivery to the desired site within a subject.